A Phase II, 5-way Cross-over Study to Evaluate the Pharmacodynamics of "Nexthaler" Dry Powder Inhaler in COPD Patients (NEXThaler)

Phase II, Partial Blind, Randomized, Placebo Controlled, 5-way Cross-over Study to Evaluate the Pharmacodynamics of BDP(Beclomethasone Diproprionate)/B17MP (Beclomethasone-17-Monoproprionate) and FORMOTEROL FUMARATE (FF) Across Two Different Dose Levels of CHF 1535 NEXThaler DPI (Dry Powder Inhaler) and CHF 1535 pMDI (Pressurized Metered-dose Inhaler)in Adult COPD (Chronic Obstructive Pumonary Disease) Patients

The study aim is to compare the pharmacodynamic effects (cardiovascular effects- primary variable: Heart rate over 4 hours post dosing- ) after administration of BDP and formoterol administered as CHF 1535 100/6 NEXThaler DPI or CHF1535 pMDI at two different dose levels.

Study Overview

• Status: Completed
• Conditions: COPD
• Intervention / Treatment: Drug: CHF 1535 NEXThaler 800/48; Drug: CHF 1535 NEXThaler PLACEBO; Drug: CHF 1535 pMDI 200/12; Drug: CHF1535 pMDI 800/48; Drug: CHF 1535 NEXThaler 200/12

Detailed Description

The effects of both formulations on serum potassium and serum glucose and the general safety and tolerability of study treatments will be also evaluated

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M239Qz
    • Medicine Evaluation Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female adults (≥ 40 and ≤ 75 years old).
• Outpatients with diagnosis of moderate/severe stable COPD, according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines update 2013 at least in the 6 months before the screening visit.
• A post-bronchodilator FEV1(Forced Expiratory Volume in one second) ≥ 40 and < 80% of the predicted normal value and FEV1/FVC (Forced Vital Capacity) < 0.7, after 4 puffs (4 x 100 µg) of salbutamol pMDI. If this criterion is not met at screening, the test can be repeated once before commencing of the run-in period.
• Ability to use pMDI (pressured metered-dose inhaler)and DPI (dry powder Inhaler) devices
• Current or past smoker of at least 10 pack/years where one pack-year is equivalent to 20 cigarettes per day for 1 year

Exclusion Criteria:

• Pregnant or lactating female subjects.
• Current diagnosis of Asthma (as defined by the current GINA (Global Initiative for Asthma guidelines 2012 (update), or history of allergic rhinitis.
• COPD exacerbations requiring systemic steroids and /or antibiotics and/or oral or nebulized beta 2-agonists in the 4 weeks prior to screening and until randomization.
• Lower Respiratory Tract Infection (LRTI) in the 4 weeks prior to screening and until randomization.
• Patients with serum potassium levels < 3.5 mEq/L (milliequivalent per liter).
• History of substance abuse or drug abuse within 12 months prior to screening visit.
• Known respiratory disorders other than COPD including but not limited to α1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, restrictive lung disease and interstitial lung disease.
• Intolerance or contra-indication to treatment with beta 2-agonists and/or inhaled corticosteroids or allergy to any component of the study treatments.
• Patients treated with non-cardioselective β-blockers in the month preceding the screening visit or during the study period.

• Patients who have clinically significant cardiovascular disease according to investigator's judgement. Thus includes but is not limited to:

  • congestive heart failure (NYHA class > 3);
  • acute ischemic heart disease within the past 12 months of screening;
  • Sustained cardiac arrhythmias (supraventricular or ventricular, >30 seconds duration) at or within 6 months of screening;
  • Non sustained cardiac arrhythmias (supraventricular or ventricular, > 3 beats < 30 seconds and or ending spontaneously and or asymptomatic);
  • History of sustained and non-sustained cardiac arrhythmias (supraventricular or ventricular);
  • 2nd or 3rd degree Atrioventricular conduction block;
  • Left Bundle Branch Block.
• An abnormal 12-lead ECG (QRS> 120 msec, PR> 220 msec, HR < 40 bpm, Heart Rate > 110 bpm) at screening or at randomization.
• Patients whose electrocardiogram (12-lead ECG) shows QTcF >450 ms for males or QTcF > 470 ms for females at screening or at randomisation.
• Patients whose DBP/SBP is higher than: DBP 90 mmHg or SBP 160 mmHg at screening or at randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: CHF 1535 NEXThaler 800/48 ug; single dose administration of CHF 1535 100/6 NEXThaler DPI, total dose: 800ug BDP, 48 ug Formoterol Fumarate	Drug: CHF 1535 NEXThaler 800/48
Placebo Comparator: CHF 1535 NEXThaler PLACEBO; single dose administration of placebo via NEXThaler DPI	Drug: CHF 1535 NEXThaler PLACEBO
Active Comparator: CHF 1535 pMDI 200/12; single dose administration of CHF 1535 100/6 pMDI , total dose: 200 ug BDP, 12 ug Formoterol Fumarate	Drug: CHF 1535 pMDI 200/12
Active Comparator: CHF 1535 100/6 pMDI 800/48; single dose administration of CHF 1535 100/6 pMDI total dose: 800ug BDP, 48 ug Formoterol Fumarate	Drug: CHF1535 pMDI 800/48
Active Comparator: CHF 1535 NEXThaler 200/12; single dose administration of CHF 1535 100/6 pMDI, total dose: 200 ug BDP, 12 ug Formoterol Fumarate	Drug: CHF 1535 NEXThaler 200/12

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Average 4-hour Heart Rate bpm (beats per minutes)	4 hours

Secondary Outcome Measures

Outcome Measure	Time Frame
QTcF (QT interval Fridericia's formula corrected) (milliseconds), QRS (milliseconds) and PR (milliseconds) intervals, PAC (Premature Atrial Contraction- percentage) burden, PVC (Premature Ventricular Contraction-percentage) burden, Blood Pressure (mmHg)	-45, -30, -15min pre-dose, 5, 10, 20, 30, 45min, 1, 1.5, 2, 3, 4, 5, 5, 7, 8, 10 12 hr post dose

Collaborators and Investigators

• Sponsor: Chiesi Farmaceutici S.p.A.
• Investigators: Principal Investigator: Dave Singh, Medicine Evaluation Unit, Manchester (UK)

Publications and helpful links

General Publications

• Singh D, Ciurlia G, Piccinno A, Muraro A, Bocchi M, Scuri M. Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study. Pulm Pharmacol Ther. 2017 Feb;42:43-51. doi: 10.1016/j.pupt.2016.12.004. Epub 2017 Jan 5.

Helpful Links

• Study Record on EU Clinical Trials Register including results
• CSR Synopsis available in the CHIESI Clinical Study Register

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: November 21, 2013
• First Submitted That Met QC Criteria: November 27, 2013
• First Posted (Estimate): December 4, 2013

Study Record Updates

• Last Update Posted (Actual): October 29, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: pharmacodynamics COPD
• Other Study ID Numbers: CCD-01535BC1-02